Selective Splitting of Substituted Bisbenzylamides and Bisbenzylamines

ABSTRACT

A process for the regioselective cleavage of secondary amines or amides is described.

The present invention relates to a process for the regioselective cleavage of secondary amines or amides to give primary amines.

Primary amines are important starting compounds or intermediates for industrial chemistry. A number of reactions are available for producing amines. Examples are the Hofmann alkylation, the reductive amination of carbonyl compounds, the reduction of nitro compounds and the Gabriel synthesis.

Chiral amines in optically active form are of particular interest, since they can be used as intermediates in many processes for producing drugs or crop protection agents. There is therefore great interest in the preparation of, in particular, optically active amines.

E. Lee-Ruff, F. J. Ablenos, Can. J. Chem., 1989, pages 699 to 702, disclose the selective oxidation of electron-rich aromatics according to the following reaction scheme. Here, a charge transfer complex between the electron-poor 2,3-dichloro-5,6-cyano-1,4-benzoquinone (DDQ) and the electron-rich substrate is formed in a first reaction step, with the resulting cationic species being able to be reacted with a nucleophile:

R. Daniel Little, Kevin D. Moeller, The Electrochemical Society Interface, Winter 2002, pages 36 to 41, disclose the electrochemical anodic oxidation of uncharged compounds of the general formula (I)

Here, a reactive cation radical (II) is firstly formed as intermediate and is converted by further elimination into a second cationic intermediate (III). The cationic intermediate (III) is subsequently reacted with a nucleophile, for example methanol. The net result is that this substituent Y in the compound (I) is replaced by a nucleophilic radical:

Examples of compounds which can be oxidized by the process described above are N-acetylated amides of the general formula (IV), which are converted by anodic oxidation and subsequent reaction with the nucleophile methanol into N-acetylated animals of the general formula (V):

The preparation of amines by regioselective cleavage of N-acetylated amides by means of electrochemical oxidation or wet chemical oxidation by 2,3-dichloro-5,6-dicyano-1,4-benzoquinone and subsequent further reaction, for example with a nucleophile, is not known.

The present invention therefore preferably has the object of providing a process for preparing primary amines from secondary amines or amides by electrochemical anodic oxidation. The process of the invention should preferably proceed with retention of the optical activity when optically active starting materials are used, so that the diastereomeric purity of the starting material can be carried over to the product.

The achievement of this object starts out from a process for the regioselective cleavage of secondary amines or amides.

The process of the invention then comprises, in a first embodiment, the following process steps:

-   -   (a′) provision of at least one secondary bisbenzylamine or         bisbenzylamide having at least one benzylic hydrogen atom in a         solvent;     -   (b′) electrochemical oxidation of the secondary amine or amide         in the presence of an electrolyte salt and reaction of the         electrolysis intermediate with a nucleophile, giving an         electrolysis product mixture;     -   (c′) work-up of the electrolysis product mixture;     -   (d′) hydrolysis of the workup electrolysis product mixture.

Primary amines can be prepared in an efficient manner by means of the process of the invention.

In the first process step of the process of the invention, at least one bisbenzylamine or bisbenzylamide having at least one benzylic hydrogen atom in a solvent is provided.

The amine or amide used in the process of the invention is, for example, a bisbenzylamine of the general formula (VI) or a bisbenzylamide of the general formula (VII):

where R⁷, R⁸, R¹⁰, R¹¹ are identical or different and are each H or C₁-C₅-alkyl and R⁹═H (VI) or R⁹=acyl (VII), with the bisbenzylamine or bisbenzylamide having at least one benzylic hydrogen atom so that at least R⁷ or R⁸ or R¹⁰ or R¹¹ is hydrogen.

As secondary amine, preference is given to using a bisbenzylamine in which the unsubstituted nitrogen function of the bisbenzylamine is provided with a protective group. The protective group is preferably selected from the group consisting of acyl groups, sulfone groups, phosphoryl groups and silyl groups. If an acyl group is used as protective group, the abovementioned bisbenzylamides of the general formula (VII) are used as starting materials.

In addition, preference is given to at least one of the benzyl rings of the bisbenzylamines or bisbenzylamides being substituted, with further preference being given to the at least one substituted benzyl ring being substituted by an electron-pushing substituent. For the purposes of the present invention, an electron-pushing substituent is a substituent which exerts a +I effect and/or a +M Effect on the benzyl ring.

The electron-pushing substituent is preferably selected from the group consisting of alkoxy groups, alkyl groups, thiolalkyl groups and halogens, with the alkyl groups preferably being selected from the group consisting of C₁-C₅-alkyls.

If an alkoxy group is used as electron-pushing substituent, it is preferably selected from the group consisting of methoxy, ethoxy, propoxy, isopropoxy, butoxy and tert-butoxy groups.

The second benzyl radical of the bisbenzylamines or bisbenzylamides is preferably either unsubstituted or substituted by an electron-pulling group. For the purposes of the present invention, an electron-pulling substituent is a substituent which exerts a −I effect and/or −M effect on the phenyl ring. Examples of suitable electron-pulling substituents are selected from the group consisting of cyano groups, nitro groups, ester groups and the halides fluorine, chlorine, bromine and iodine.

The classification of aromatic substituents into substituents having a +I and −I effect or a +M effect and −M effect is known per se to those skilled in the art. Further details may be found in Beyer/Walter, “Lehrbuch der Organischen Chemie”, 1998, 23rd revised and updated edition, pages 515-518, whose disclosure on the subject is incorporated by reference into the present invention.

In process step (a′), the secondary amine or amide is provided in a solvent. In a particularly preferred embodiment, the solvent is an organic solvent, preferably an organic nucleophilic solvent. Further preference is given to the solvent being selected from the group consisting of protic polar solvents such as alcohols, aliphatic carboxylic acids such as acetic acid and water.

If an alcohol is used as solvent, it is, for example, methanol, ethanol, n- or i-propanol or butanols. Preference is given to methanol.

In a further embodiment of the present invention, mixtures of the abovementioned solvents can also be used.

If appropriate, customary cosolvents are added to the electrolysis solution. These are the inert solvents having a high oxidation potential which are generally customary in organic chemistry. Examples which may be mentioned are dimethyl carbonate, propylene carbonate, ethylene carbonate, tetrahydrofuran, dimethoxyethane, dichloromethane, trichloromethane, tetrachloromethane and acetonitrile.

In process step (b′), an electrochemical oxidation of the secondary amine or amide and a reaction of the electrolysis intermediate with a nucleophile take place, giving an electrolysis product mixture.

An electrolyte salt is necessary as depolarizer for the electrochemical oxidation, and this is added to the solution provided in process step (a′).

Electrolyte salts present in the electrolysis solution are generally alkali metal salts, alkaline earth metal salts, tetra(C₁-C₆-alkyl)ammonium salts, preferably tri(C₁-C₆-alkyl)-methylammonium salts. Possible counterions are sulfate, hydrogensulfate, alkyl sulfates, aryl sulfates, halides, phosphates, carbonates, alkyl phosphates, alkyl carbonates, nitrate, alkoxides, tetrafluoroborate, hexafluorophosphate or perchlorate.

Furthermore, the acids derived from the abovementioned anions are also possible as electrolyte salts.

In addition, ionic liquids are also suitable as electrolyte salts. Suitable ionic liquids are described in “Ionic Liquids in Synthesis”, edited by Peter Wasserscheid, Tom Welton, Verlag Wiley VCH, 2003, chapters 1 to 3, and in DE-A-10 2004 011427.

In particular, strong mineral acids and sulfonic acids are suitable as electrolyte salts for the purposes of the present invention. Examples are H₂SO₄, H₃PO₄. methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid. For the purposes of the present invention, the use of H₂SO₄ is particularly preferred.

The concentration of the electrolyte salt is generally 0.0001-5 mol/l, preferably 0.001-1 mol/l, particularly preferably 0.001-0.1 mol/l, very particularly preferably 0.005-0.05 mol/l.

The process conditions for electrochemical oxidation in respect of temperature, electrolysis time, current and concentration of the secondary amines or amides are dependent on the starting material used, in particular bisbenzylamine or bisbenzylamide, and on the solvent used.

The electrolysis is carried out in customary electrolysis cells known to those skilled in the art. Suitable electrolysis cells are known to those skilled in the art. The electrolysis is preferably carried out continuously using undivided flow cells or batchwise in glass beaker cells at reaction volumes of <100 ml.

Very particularly useful cells are bipolar capillary cells or plate stack cells in which the electrodes are configured as plates and are arranged parallel to one another (cf. Ullmann's Encyclopedia of Industrial Chemistry, 1999 electronic release, sixth edition, VCH-Verlag Weinheim, Volume Electrochemistry, chapter 3.5. special cell designs and chapter 5, Organic Electrochemistry, subchapter 5.4.3.2 Cell Design).

The current densities at which the process is carried out are generally from 1 to 1000 mA/cm², preferably from 10 to 100 mA/cm². The temperatures are usually from −20 to 60° C., preferably from 10 to 60° C. The process is generally carried out at atmospheric pressure. Higher pressures are preferably employed when the process is to be carried out at relatively high temperatures, so as to avoid boiling of the starting compounds or cosolvents.

Suitable anode materials are, for example, graphite, carbon, noble metals such as platinum, metal oxides such as ruthenium oxide or chromium oxide, mixed oxides of the type RuO_(x)TiO_(x) and diamond electrodes. Preference is given to graphite or carbon electrodes.

Possible cathode materials are, for example, iron, steel, stainless steel, nickel, noble metals such as platinum, graphite, carbon materials and diamond electrodes. Preference is given to the systems graphite as anode and cathode, graphite as anode and nickel, stainless steel or steel as cathode and platinum as anode and cathode.

Furthermore, the electrochemical oxidation is carried out until the benzylamide used as starting material has completely reacted or most of it has reacted. For the purposes of the present invention, the term “mostly reacted” means a conversion of preferably more than 90%. The progress of the reaction is monitored by means of customary laboratory methods (e.g. gas chromatography or thin layer chromatography). A multiple of the theoretical amount of charge of 2 F/mol of amide can often be necessary to achieve complete conversion.

Furthermore, the concentration of the starting material to be oxidized in the solution to be electrolyzed is preferably from 0.00001 to 5 mol/l, particularly preferably from 0.0001 to 3 mol/l, in particular from 0.001 to 2 mol/l.

The electrochemical oxidation provided in process step (b′) results in oxidation of the nitrogen function of the secondary amine or amide and formation of a radical cation. The electrochemical oxidation preferably occurs on the side of the amine or amide on which the more stable radical is formed. This is the side of the secondary amine or amide at which the benzyl ring having the electron-pushing substituent is located. The regioselectivity is achieved, in particular, in the case of substrates having alkoxy, thioalkyl or alkyl groups.

In process step (b′), a reaction of the electrolysis intermediate with a nucleophile occurs immediately after the electrochemical oxidation.

The electrolysis product mixture is preferably reacted with a nucleophile selected from the group consisting of methanol, acetic acid and water.

The nucleophile used is preferably the solvent used in process step (a′), so that addition of a further nucleophile can be dispensed with.

The process of the invention in a first embodiment is preferably suitable for the electrochemical oxidation of optically active, i.e. diastereomeric, bisbenzyiamines or bisbenzylamides, since the stereochemical purity of the resulting product is not significantly changed by the electrochemical oxidation. For the purposes of the present invention, “not significantly changed” means that the optical purity of the product differs from the optical purity of the starting material by not more than 10%, particularly preferably not more than 5%, in particular not more than 3%.

A work-up of the electrolysis product mixture is carried out in process step (c′).

Here, the electrolysis product mixture resulting from process step (b′) is preferably worked up by means of the following process steps:

-   -   (c′1) removal of the solvent and addition of water, an organic         solvent selected from the group consisting of dichloromethane;         chloroform; ethers such as diethyl ether, tert-butyl methyl         ether; esters such as ethyl acetate; hydrocarbons such as         toluene, xylene or cyclohexane and an acid;     -   (c′2) extraction of the mixture resulting from process step         (c′1) with an organic solvent selected from the group consisting         of dichloromethane; chloroform; ethers such as diethyl ether,         tert-butyl methyl ether; esters such as ethyl acetate;         hydrocarbons such as toluene, xylene or cyclohexane;     -   (c′3) drying of the resulting organic phases;     -   (c′4) removal of the organic solvent.

Any suitable acid can be used in process step (c′1). Suitable acids are known to those skilled in the art. Examples are hydrochloric acid, sulfuric acid, phosphoric acid and nitric acid. Preference is given to using 10% strength hydrochloric acid.

Drying of the organic phases in process step (c′3) is carried out, for example, over sodium carbonate or sodium sulfate. As an alternative, it is also possible to use all further customary desiccants.

In process step (c′4), the organic solvent is preferably removed by distillation.

In process step (d′), the electrolysis product mixture which has been worked up is hydrolyzed.

The hydrolysis of the electrolysis product mixture which has been worked up is preferably effected using a mixture of sodium hydroxide solution or potassium hydroxide solution and triethanolamine. The use of 50% strength sodium or potassium hydroxide solution is preferred. Here, the content of 50% strength sodium hydroxide solution in the mixture is preferably from 10 to 50% by weight, particularly preferably from 20 to 40% by weight, in particular from 25 to 35% by weight. The content of triethanolamine in the mixture is preferably from 10 to 50% by weight, particularly preferably from 20 to 40% by weight, in particular from 25 to 35% by weight. The primary amine is formed in the hydrolysis.

In a second embodiment, the present invention provides a “wet chemical” process for the regioselective cleavage of secondary amines or amides.

The process of the invention in this second embodiment then comprises the following process steps:

-   -   (a″) provision of at least one secondary bisbenzylamine or         bisbenzylamide having at least one benzylic hydrogen atom in a         solvent, with the solvent optionally comprising a nucleophile;     -   (b″) oxidation of the secondary amine or amide by means of         2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), giving an         oxidation product mixture;     -   (c″) reaction of the oxidation product mixture with a         nucleophile.

In process step (a″), at least one secondary amine or amide in a solvent is provided, with the solvent optionally comprising a nucleophile.

As regards the starting materials to be used, viz. secondary amine or amide, reference is made to what has been said above in respect of the first embodiment of the process of the invention. However, preference is given to at least one benzyl ring of the bisbenzylamines or bisbenzylamides which are preferably used as starting materials bearing an alkoxy substituent. Particular preference is given to the alkoxy substituent being selected from the group consisting of methoxy, ethoxy, propoxy, isopropoxy, butoxy and tert-butoxy.

The solvent used in process step (a″) is preferably selected from the group consisting of dichloromethane, chloroform; 1,2-dichloroethane, tert-butyl methyl ether, acetonitrile, toluene and xylene.

Preference is also given to the solvent being used in admixture with a nucleophile such as water, for example distilled water, an alcohol, for example methanol, ethanol, n-propanol, i-propanol or butanol. Suitable mixtures are, for example, mixtures of 1,2-dichloroethane with water in a ratio of from 100:1 to 1:1, particularly preferably from 20:1 to 5:1, in particular from 12:1 to 8:1.

Process step (b″) comprises the oxidation of the secondary amine or amide by means of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), giving an oxidation product mixture. The oxidation provided in process step (b″) of the secondary amine or amide is preferably carried out by adding DDQ to the starting material to be oxidized, which is present in the above-described solvent, if appropriate in the presence of a nucleophile.

The oxidation is preferably carried out with stirring at a temperature of from −10° C. to 150° C., particularly preferably from 20 to 100° C., in particular from 60 to 90° C. The reaction time under these preferred conditions is preferably from 0.2 to 24 hours, particularly preferably from 1 to 12 hours, in particular from 5 to 10 hours.

In process step (c″), the oxidation product mixture is reacted with a nucleophile. This is effected by addition of the optionally dissolved nucleophile to the oxidation product mixture.

Suitable nucleophiles are, for example, water, alcohols such as methanol, ethanol or propanol.

As mentioned above, the amine or amide to be oxidized can be provided in a solvent in admixture with a nucleophile in process step (a″). As a result, the oxidized amine or amide reacts immediately with the nucleophile present after it has been oxidized in process step (b″), so that further addition of the nucleophile can be dispensed with.

The product resulting from process step (c″) can, for example, be worked up by washing with saturated sodium carbonate solution and/or saturated sodium chloride solution, extraction of the resulting aqueous phases with an organic solvent, drying of the combined organic phases, for example over sodium sulfate, and concentration, for example under reduced pressure.

The second embodiment of the process of the invention also leads to regioselective cleavage of the secondary amines or amides used as starting materials. Thus, the regioselective oxidation in the second embodiment of the process of the invention occurs on the more electron-rich benzyl ring.

This second embodiment of the process of the invention is therefore likewise suitable for the electrochemical oxidation of optically active, i.e. diastereomeric, bisbenzylamines or bisbenzylamides, since the stereochemical purity of the resulting products is not significantly changed by the oxidation by means of DDQ. For the purposes of the present invention, “not significantly changed” means that the optical purity of the product differs from the optical purity of the starting material by not more than 10%, particularly preferably not more than 5%, in particular not more than 2%.

The present invention further provides for the use of 2,3-dichloro-5,6-benzoquinone for the regioselective oxidation of secondary bisbenzylamines or bisbenzylamides having at least one benzylic hydrogen atom.

The secondary bisbenzylamides used as starting material in the process of the invention in its first and second embodiments can, for example, be prepared by reacting secondary bisbenzylamines with acetic anhydride.

Here, particular mention may be made of the following process steps:

-   -   (1) addition of acetic anhydride to the secondary amine or         addition of the secondary amine to acetic anhydride, resulting         in a reaction mixture I;     -   (2) stirring of the resulting reaction mixture I for a period of         preferably from 0.5 to 24 hours, particularly preferably from 1         to 15 hours, in particular from 1 to 2 hours, resulting in a         reaction mixture II;     -   (3) hydrolysis of the reaction mixture II resulting from process         step (2) and extraction of the resulting aqueous solution with         an organic solvent, resulting in an organic phase;     -   (4) if appropriate, removal of acetic anhydride present in the         organic phase.

The addition of acetic anhydride to the secondary amine can be carried out at a temperature of preferably from 0 to 100° C., particularly preferably from 10 to 50° C., in particular from 20 to 30° C.

The resulting reaction mixture I is stirred at a temperature of preferably from 0 to 150° C., particularly preferably from 50 to 120° C., in particular from 80 to 100° C.

The removal of acetic anhydride present in the organic phase can, for example, be effected by addition of a base, with the base preferably being present in an aqueous solution. The base can be, for example, sodium carbonate.

If appropriate, the process step (3) or, if appropriate, the process step (4) can be followed by the following process steps (5) and (6):

-   -   (5) treatment of the organic phase while stirring with a mixture         of an organic solvent selected from the group consisting of         ethers and optionally halogenated hydrocarbons and water for a         period of preferably from 0.1 to 24 hours, particularly         preferably from 0.5 to 4 hours, in particular from 0.5 to 2         hours, and     -   (6) separation of the organic and aqueous phases, if appropriate         multiple shaking of the aqueous phase with an organic solvent,         drying of the combined organic phases and removal of the organic         solvent.

The present invention further provides for the use of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone for the regioselective oxidation of secondary bisbenzylamines or bisbenzylamides having at least one benzylic hydrogen atom.

The present invention is illustrated by the following examples which do not, however, restrict the scope of the present invention.

EXAMPLES

1. General Procedure for the Preparation of Secondary Amides

5.5 ml of acetic anhydride are added dropwise to 23.5 mmol of the amine at room temperature. 20 minutes after the addition is complete, the temperature is increased to 90° C. for a period of 30 minutes while stirring. The solution is poured into 20 ml of cold water, admixed with 20 ml of ether and the resulting phases are separated. The combined extracts are dried over Na₂SO₄ and concentrated under reduced pressure.

To remove the unreacted acetic anhydride, 10 ml of a saturated aqueous solution of Na₂CO₃ are added to the unpurified reaction product. The resulting mixture is then admixed with 15 ml of ether and 10 ml of water, stirred for 30 minutes and the resulting aqueous phase is extracted a number of times with ether (3-15 ml). The combined extracts are dried over Na₂SO₄ and concentrated under reduced pressure.

The diastereomeric purity is determined by means of gas chromatography. a) N-[1-(4-Methoxyphenyl)ethyl]-N-(1-phenylethyl)acetamide R,R isomer: 92.7% R,S isomer: 7.3% b) N-[1-(2-Methoxyphenyl)ethyl]-N-(1-phenylethyl)acetamide R,R isomer: 96.0% R,S isomer: 4.0% ¹H-NMR (400 MHz, CDCl₃): δ = 1.6 (3H, m); 1.8 (3H, m); 2.4 (3H, s); 3.7 (3H, s); 4.2 (1H, q); 5.4 (1H, q); 6.4-7.4 (9H, aromatic). c) N-[1-Phenylethyl]-N-(1-o-tolylethyl)acetamide R,R isomer: 87.0% R,S isomer: 13.0% ¹H-NMR (400 MHz, CDCl₃): δ = 1.4-1.6 (6H, m); 1.8 (3H, m); 2.4 (3H, s); 4.1 (1H, q); 4.2 (1H, q); 6.5-7.5 (9H, aromatic). d) N-[1-(2,4-Dimethoxyphenyl)ethyl](1-phenylethyl)acetamide R,R isomer: 96.6% R,S isomer: 3.4% ¹H-NMR (400 MHz, CDCl₃): δ = 1.6 (3H, m); 1.8 (3H, m); 2.3 (3H, s); 3.6 (3H, s); 4.3 (1H, q); 5.3 (1H, q); 6.3-7.4 (8H, aromatic). e) N-[1-(4-Chlorophenyl)ethyl](1-phenylethyl)acetamide R_(f) (silica gel): 0.44 (ethyl acetate:cyclohexane = 1:1) f) N-[1-Phenylethyl]-N-(1-p-tolylethyl)acetamide S,S isomer: 87.5% S,R isomer: 12.5% ¹H-NMR (400 MHz, CDCl₃): δ = 1.6-1.7 (6H, d); 1.9 (3H, s); 2.3 (3H, s); 4.8 (1H, br); 5.8 (1H, br); 6.8-7.5 (9H, aromatic). g) N-[1-(4-Methoxyphenyl)ethyl]-N-(1-pyridin-3-yl-ethyl)acetamide R,R isomer: 88.0% R,S isomer: 12.0%

2. Electrochemical Oxidation

8.4 mmol of the amide prepared under 1.) are dissolved in 47 g of methanol, admixed with 0.5 g of concentrated sulfuric acid (96%) and transferred to an undivided glass beaker cell provided with two graphite electrodes (20×70 mm, immersion depth: 50 mm, type: MKUS F04, manufactured by SGL Carbon, Meitingen, Germany) at a spacing of 10 mm. The mixture is heated to 40° C. while stirring and electrolyzed at a current density of 34 mA/cm² until most of the amide has reacted (1.0-4.5 hours corresponding to from about 2 F/mol of amide to about 16 F/mol of amide, corresponding to from about 100% to 800% of the theoretical amount of charge required). The methanol is removed under reduced pressure and the residue is admixed with 25 ml of water, 50 ml of dichloromethane and 10 ml of 10% strength hydrochloric acid. The aqueous phase is extracted a number of times with dichloromethane (3·20 ml). The combined extracts are dried over Na₂SO₄ and the solvent is removed. The crude yield of amide is 80%.

12 mmol of triethanolamine and 22.5 mmol of 50% strength NaOH are added to 6.7 mmol of the amide mixture and the resulting mixture is stirred at 120° C. for 3 hours. 20 ml of ether and 15 ml of water are added to the mixture. The aqueous phase is extracted with ether (3·15 ml). The combined extracts are dried over Na₂SO₄, the solvent is removed under reduced pressure and the residue is examined by GC and ¹H-NMR. a) N-[1-(4-Methoxyphenyl)ethyl]-N-(1-phenylethyl)acetamide (dr = 93:7) 77.5% of N-1-phenylethylacetamide 10.9% of p-methoxyacetophenone 11.6% of 1-methoxy-4-(1-methoxyethyl)benzene ¹H-NMR (400 MHz, CDCl₃): δ = 1.4 (3H, d); 1.5 (3H, d); 2.0 (3H, s); 2.6 (3H, s); 3.8 (3H, s); 3.9 (3H, s); 4.2 (1H, q); 5.2 (1H, q); 5.7 (1H, br); 6.9-8.0 (13H, aromatic). Optical purity:   92% of R-1-phenylethylamine   8% of S-1-phenylethylamine b) N-[1-(2-Methoxyphenyl)ethyl]-N-(1-phenylethyl)acetamide (dr = 87:13) 100% of N-1-phenylethylacetamide ¹H-NMR (400 MHz, CDCl₃): δ = 1.35 (3H, m); 2.0 (3H, s); 5.1 (1H, q); 5.8 (1H, br); 7.2-7.3 (5H, aromatic). c) N-[1-Phenylethyl]-N-(1-o-tolylethyl)acetamide (dr: 87:13)   65% of 1-phenylethylamine   35% of 1-p-tolylethylamine ¹H-NMR (400 MHz, CDCl₃): δ = 1.3 (6H, m); 1.6 (4H, br); 2.3 (3H, s); 4.2 (1H, q); 4.4 (1H, q); 7.1-7.5 (9H, aromatic). Optical purity: 89.3% of R-1-phenylethylamine 10.7% of S-1-phenylethylamine d) N-[1-(2,4-Dimethoxyphenyl)ethyl](1-phenylethyl)acetamide  100% of 1-phenylethylamine e) N-[1-(4-Chlorophenyl)ethyl](1-phenylethyl)acetamide 74.8% of 1-phenylethylamine 25.2% of 1-(4-chlorophenyl)ethylamine ¹H-NMR (400 MHz, CDCl₃): δ = 1.4-1.5 (6H, m); 1.6 (4H, br); 4.1 (2H, m); 7.2-7.4 (9H, aromatic). f) N-[1-Phenylethyl]-N-(1-p-tolylethyl)acetamide (dr: 87.5:12.5)   90% of 1-phenylethylamine   10% of 1-p-tolylethylamine ¹H-NMR (400 MHz, CDCl₃): δ = 1.5 (3H, d); 2.0 (3H, s); 5.2 (1H, q); 5.7 (1H, br); 7.3-7.4 (5H, aromatic). Optical purity: 89.3% of R-1-phenylethylamine 10.7% of S-1-Phenylethylamine

3. Oxidation By Means of DDQ

1.8 g (6 mmol) of N-[1-(4-methoxyphenyl)ethyl]-N-(1-phenylethyl)acetamide (dr: 82:18) are dissolved in 20 ml of 1,2-dichloroethane:water/10:1 (v/v). 2.1 g (9 mmol) of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone are added and the resulting mixture is refluxed for 7 hours. The mixture is washed with 20 ml of a saturated Na₂CO₃ solution and 15 ml of a saturated NaCl solution. The combined aqueous phases are extracted a number of times with 1,2-dichloroethane (3×15 ml). The combined organic phases are dried over Na₂SO₄ and concentrated under reduced pressure.

The residue consists of a mixture of N-1-phenylethylacetamide (37 GC-% by area) and 4-methoxyacetophenone (63 GC-% by area). The optical purity of the N-1-phenylethyl-acetamide is: R—N-1-phenylethylacetamide: 81.8% S—N-1-phenylethylacetamide: 18.2% 

1. A process for the regioselective cleavage of secondary amines or amides, which comprises the following process steps: (a′) provision of at least one secondary bisbenzylamine or bisbenzylamide having at least one benzylic hydrogen atom in a solvent; (b′) electrochemical oxidation of the secondary amine or amide in the presence of an electrolyte salt and reaction of the electrolysis intermediate with a nucleophile, giving an electrolysis product mixture; (c′) work-up of the electrolysis product mixture; (d′) hydrolysis of the workup electrolysis product mixture.
 2. (canceled)
 3. The process according to claim 1, wherein at least one benzyl ring of the bisbenzylamines or bisbenzylamides is substituted by an electron-pushing substituent which exerts a +I effect and/or a +M effect on the benzyl ring.
 4. The process according to claim 1, wherein a nucleophilic solvent selected from the group consisting of methanol, ethanol, n-propanol, i-propanol and butanol is used in process step (a).
 5. The process according to claim 1, wherein the electrochemical oxidation is carried out under at least one of the following conditions: a temperature of from −20 to 60° C.; a current density of from 1 to 1000 mA/cm²; a concentration of the electrolyte salt of from 0.0001 to 5 mol/l.
 6. The process according to any of claim 1, wherein the electrolysis solution is worked up as follows in (c′): (c′1) removal of the solvent and addition of water, an organic solvent selected from the group consisting of dichloromethane, chloroform, ethers, esters and hydrocarbons, and an acid; (c′2) extraction of the mixture resulting from process step (c′1) with an organic solvent selected from the group consisting of dichloromethane, chloroform, ethers, esters and hydrocarbons; (c′3) drying of the resulting organic phases; and (c′4) removal of the organic solvent.
 7. The process according to claim 1, wherein the hydrolysis in (d′) is effected by means of a mixture of sodium hydroxide solution or potassium hydroxide solution and triethanolamine.
 8. The process according to claim 1, wherein diastereomeric secondary amines or amides are used and the stereochemical purity of the resulting products is not significantly changed by the oxidation.
 9. A method of regioselective oxidation comprising oxidating secondary bisbenzylamines or bisbenzylamides having at least one benzylic hydrogen atom.
 10. A process for the regioselective cleavage of secondary amines or amides, which comprises the following process steps: (a″) provision of at least one secondary bisbenzylamine or bisbenzylamide having at least one benzylic hydrogen atom in a solvent, with the solvent optionally comprising a nucleophile; (b″) oxidation of the secondary amine or amide by means of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), giving an oxidation product mixture; (c″) reaction of the oxidation product mixture with a nucleophile.
 11. The process according to claim 10, wherein at least one benzyl ring of the bisbenzylamines or bisbenzylamides is substituted by an electron-pushing substituent which exerts a +I effect and/or a +M effect on the benzyl ring.
 12. The process according to claim 11, wherein a nucleophilic solvent selected from the group consisting of methanol, ethanol, n-propanol, i-propanol and butanol is used in process step (a).
 13. The process according to claim 11, wherein the electrochemical oxidation is carried out under at least one of the following conditions: a temperature of from −20 to 60° C.; a current density of from 1 to 1000 mA/cm²; a concentration of the electrolyte salt of from 0.0001 to 5 mol/l.
 14. The process according to claim 12, wherein the electrochemical oxidation is carried out under at least one of the following conditions: a temperature of from −20 to 60° C.; a current density of from 1 to 1000 mA/cm²; a concentration of the electrolyte salt of from 0.0001 to 5 mol/l.
 15. The process according to claim 11, wherein the electrolysis solution is worked up as follows in process step (c′): (c′1) removal of the solvent and addition of water, an organic solvent selected from the group consisting of dichloromethane, chloroform, ethers, esters and hydrocarbons, and an acid; (c′2) extraction of the mixture resulting from process step (c′1) with an organic solvent selected from the group consisting of dichloromethane, chloroform, ethers, esters and hydrocarbons; (c′3) drying of the resulting organic phases; (c′4) removal of the organic solvent.
 16. The process according to claim 12, wherein the electrolysis solution is worked up as follows in process step (c′): (c′1) removal of the solvent and addition of water, an organic solvent selected from the group consisting of dichloromethane, chloroform, ethers, esters and hydrocarbons, and an acid; (c′2) extraction of the mixture resulting from process step (c′1) with an organic solvent selected from the group consisting of dichloromethane, chloroform, ethers, esters and hydrocarbons; (c′3) drying of the resulting organic phases; (c′4) removal of the organic solvent.
 17. The process according to claim 13, wherein the electrolysis solution is worked up as follows in process step (c′): (c′1) removal of the solvent and addition of water, an organic solvent selected from the group consisting of dichloromethane, chloroform, ethers, esters and hydrocarbons, and an acid; (c′2) extraction of the mixture resulting from process step (c′1) with an organic solvent selected from the group consisting of dichloromethane, chloroform, ethers, esters and hydrocarbons; (c′3) drying of the resulting organic phases; (c′4) removal of the organic solvent.
 18. The process according to claim 1 1, wherein the hydrolysis in process step (d′) is effected by means of a mixture of sodium hydroxide solution or potassium hydroxide solution and triethanolamine.
 19. The process according to claim 12, wherein the hydrolysis in process step (d′) is effected by means of a mixture of sodium hydroxide solution or potassium hydroxide solution and triethanolamine.
 20. The process according to claim 13, wherein the hydrolysis in process step (d′) is effected by means of a mixture of sodium hydroxide solution or potassium hydroxide solution and triethanolamine. 